According to French researchers, intravitreal anti-vascular endothelial growth factor (anti-VEGF) medications in general do not appear to increase the risk of extraocular hemorrhagic or other adverse events, though questions remain

In a paper online March 22 in JAMA Ophthalmology, Dr. Marie Thulliez of Bretonneau Hospital, in Tours, and colleagues note that the systemic safety of agents such as ranibizumab, bevacizumab, aflibercept, and pegaptanib is not yet well established.

The team identified 21 meta-analyses covering 57 randomized controlled trials, 76 prospective or retrospective cohorts or case-series, and two population-based cohort studies. Intravitreal anti-VEGF treatments were given to patients with neovascular age-related macular degeneration, diabetic macular edema, or retinal vein occlusion.

Only one meta-analysis showed an increase in the two-year rates of overall and vascular mortality with high-dose aflibercept and ranibizumab. However, the number of events was "very low," and the study had other shortcomings, Dr. Thulliez and colleagues note.

Nevertheless, they also point out that "enrollment criteria in many of the trials tended to bias the results toward a lower incidence of adverse events because patients with cardiovascular diseases were often excluded."

And they point out that, "Compared with control treatments, ranibizumab may be associated with an increase in the risk of nonocular hemorrhage in patients with age-related macular degeneration." This was seen in several meta-analyses.

In general, the team concludes, "Anti-VEGF treatments did not increase the risk of systemic adverse events when compared with control regimens."

Dr. Marco A. Zarbin of Rutgers New Jersey Medical School Institute of Ophthalmology and Visual Science, Newark, who has reviewed the use of anti-VEGF injections, told Reuters Health by email that some studies show mildly increased risk.

"I think the overall conclusion is that these agents are safe for most people, but there may be a subset of patients for whom these agents pose an increased risk of significant systemic vascular events after intravitreal anti-VEGF injection," said Dr. Zarbin, who was not involved in the study.

Dr. Shriji Patel, assistant professor in ophthalmology at the Vanderbilt Eye Institute, in Nashville, Tennessee, said the study "rigorously analyzes the high-quality data available on this subject.

As the authors point out, the existing data suffer from various biases along with heterogeneity in systemic adverse events reporting. However, their findings confirm what the consensus is on this matter – intravitreal administration of anti-VEGF agents does not increase the risk of systemic adverse events."